The immune system is responsible for distinguishing between self and non-self in living organisms, and protecting the self by eliminating the non-self. The immune system has an elaborate regulatory function to minimize its aggressiveness to the cells (components) of self. It is thought, however, that if the regulatory function fails, an attack on the cells (components) of itself, i.e., an autoimmune disease, develops. Autoimmune diseases are roughly divided into systemic autoimmune diseases and organ-specific autoimmune diseases. The organ-specific autoimmune diseases of these refer to diseases accompanying chronic inflammation in a particular organ or tissue (brain, liver, eyes, and articular), which is considered to be caused by immune responses to an autoantigen specific for the organ (autoimmune responses). Representative diseases include multiple sclerosis (brain, spinal cord) and rheumatoid arthritis (articular). Although different organs are affected, these diseases are thought to share the collapse of the balance of the immune system by helper T (Th) cells, resulting in a shift toward the Th1 type, as a common causal factor. Therapies for these diseases basically commonly focus on adjusting the biased immune balance of helper T cells to a shift toward the type Th2.
Natural killer (NK) T cells are immunocytes belonging to a new lymphocyte lineage that exhibit characteristics different from those of other lymphocyte lineages (T, B, and NK cells). NKT cells are related to NK cells because cytotoxic perforin granules are present therein (non-patent document 1). However, because NKT cells express not only NK cell markers, but also T cell receptors (TCRs), they have been shown to represent a new class of cells that are distinct from known cells (non-patent document 2). NKT cells are capable of producing both type Th1 cytokines (mainly interferon (IFN)-γ), which are produced by type Th1 helper T cells, and type Th2 cytokines (mainly interleukin (IL)-4), which are produced by type Th2 helper T cells (non-patent document 3); it is suggested that the balance of the immune system may be adjusted thereby (non-patent document 4). Therefore, it is possible to adjust the collapsed balance of the immune system by controlling the function of NKT cells.
The characteristic of NKT cells that is attracting the greatest attention resides in the fact that the a chain of TCR expressed in NKT cells is constant within the same species. This essentially shows that all NKT cells of the same species of organism are activated by the same substance. As such, the α chain is Vα24 for humans and Vα14 for murine animals, there is a very high homology between the two species. For the β chain, which forms a pair with the α chain, only a very limited number of kinds are known, so this TCR is called “invariable TCR”.
A wide variety of sphingoglycolipids are known to exist in living organisms. Sphingoglycolipids in living organisms, generally comprising various sugars bound to ceramides via β-bonds, are present in the cell membranes of various organs, though their abundance varies among different organs (non-patent document 5). Meanwhile, it has been reported that sphingoglycolipids comprising sugars bound to ceramides via α-bonds possesses potent immunopotentiating action and antitumor activity (non-patent document 6). α-Galactosylceramides, typified by agelasphins, are glycolipids isolated from extracts from Agelas mauritianus, one kind of sponge, and are known to potently activate NKT cells (non-patent document 4). α-Galactosylceramides are sphingoglycolipids comprising a ceramide resulting from the acylation of the sphingosine base by a long-chain fatty acid, and galactose bound thereto in α-configuration. After being incorporated in antigen presenting cells (APCs), typified by dendritic cells (DCs) and the like, they are presented onto the cell membrane by the CD1d protein, which belongs to major histocompatibility gene complex (MHC) class I molecules. NKT cells become activated by recognizing the thus-presented complex of the CD1d protein and α-glycosylceramide by means of TCR, and various immune reactions are initiated. To date, various analogues have been synthesized, and have been investigated for the correlation between the structure and activity thereof; it has been demonstrated that α-GalCer (compound a), developed by Kirin Brewery Co., Ltd., out of the series of synthetic analogues, exhibits the highest activity, and that the corresponding β-form (β-GalCer) has no immunomodulating activity.
In recent years, with a focus on the above-described functions of NKT cells, a therapeutic drug containing α-GalCer as an active ingredient has been proposed and developed. However, administration of α-GalCer induces the production of IL-4, a cytokine that suppresses autoimmune diseases, as desired, but at the same time it induces the production of IFN-γ, a cytokine that exacerbates autoimmune diseases. As a result, the effects of both are cancelled each other, posing the problem of a lack of therapeutic effect on autoimmune diseases.
A group of Yamamura et al. recently developed OCH (compound b), a glycolipid that induces NKT cells to preferentially produce IL-4, a cytokine that suppresses autoimmune diseases (patent document 1, non-patent documents 7, 8 and 9). OCH is reported to induce the preferential production of IL-4 by shortening the alkyl side chain of α-GalCer to weaken the interaction thereof with the CD1d protein. However, this method is faulty in that the time of activation of NKT cells is short because the stability of the complex of the ligand OCH and the CD1d protein is low, and the absolute amount of IL-4 produced is small. For this reason, it is problematic that a large amount of OCH must be administered to obtain a desired effect.
Furthermore, a report is available concluding that glycolipids having an aliphatic amide group or an aliphatic sulfonamide group are useful as immunomodulator (patent document 2). However, cytokine production by such glycolipids has not been demonstrated, nor is there any suggestion of the selectivity thereof.
patent reference 1: WO 2003/016326
patent reference 2: JP-A-2001-354666
non-patent reference 1: Proc. Natl. Acad. Sci. USA 1998, 95, 5690-5693
non-patent reference 2: J. Immunol. 1995, 155, 2972-2983
non-patent reference 3: J. Immunol. 1998, 161, 3271-3281
non-patent reference 4: Science, 1997, 278, 1626-1629
non-patent reference 5: Biochim. Biophys. Acta 1973, 315-335
non-patent reference 6: J. Med. Chem. 1995, 38, 2176-2187
non-patent reference 7: J. Org. Chem. 2005, 70, 2398-2401
non-patent reference 8: Tetrahedron Lett. 2005, 46, 5043-5047
non-patent reference 9: Nature 2001, 413, 531-534